More than 575,000 Americans have end-stage renal disease, which is typically complicated by anemia, and most of these patients receive maintenance dialysis treatment. The proposed work will compare the effectiveness and safety of darbepoetin alfa, a novel injectible drug for the treatment of anemia, with its established cousin, epoetin alfa. Similarly, ferumoxytol, a new intravenous iron supplement for the treatment of anemia will be compared with an established iron supplement, iron sucrose. Both drugs were approved using information from randomized studies that evaluated their efficacy on reducing anemia. Very limited information, however, is available for either drug regarding their longer-term efficacy and safety. We are proposing to study the effectiveness and safety of these two medications when compared to their established cousins. Events of scientific interest include short-term outcomes (anaphylaxis, laboratory parameters including hemoglobin, iron saturation, ferritin) and longer- term outcomes including infection, cardiovascular events, cancer, and mortality. We will use already collected data from Medicare billing claims and electronic medical records of dialysis providers to address these research questions. Since facilities choose among these treatment options based on what is available in their formulary, and not necessarily based on patient characteristics, we can exploit natural experiments that occur when facilities switch their ESA or iron agent for their entire patient population. We will apply modern epidemiological techniques to eliminate bias and aspire to provide valid estimates of relative benefits and risks. Findings from the proposed work have the potential to immediately impact and improve the care that patients with end-stage renal disease receive. Our results may improve the quality of care received and, thus, the outcomes of this vulnerable patient population. The aims and scope of work are in full congruence with the mission of the National Institutes of Diabetes and Digestive and Kidney Diseases, and more specifically the Division of Kidney, Urologic, and Hematologic Diseases, which will consider this application for funding.